HU201053B - Process for production of guanidin carbonic acid esthers and medical compositions containing them - Google Patents

Abstract

Novel guanidinecarboxylic acid esters of the formula I …<IMAGE>… and a preparation process for these compounds are described. The compounds according to the invention are H2 agonists possibly having an additional H1 antagonist component, which are distinguished by improved oral activity. The pharmaceutical use of the guanidinecarboxylic acid esters mentioned and medicines containing these esters are furthermore described.

Description

HU 201053 Β

The present invention relates to novel guanidine derivatives and to pharmaceutical compositions containing them.

Histamine H ₂ antagonists, such as impromidine (GJ. Durant et al., London, 1978, 276, 403) significantly increase contractile capacity by stimulating the heart's H2 receptors and, by virtue of their positive inotropic action, are especially for the treatment of myocardial hypertension.

A 35.12.084, 35.28.214. and 35.28.215. German Patent Publication No. 0.199,845; European Patent Application Publication No. 2,972,125 discloses H ₂ antagonists which, by incorporating additional H ₁ antagonistic building blocks, can both eliminate the undesirable side effects of impromidine and significantly increase the potency of the compounds. These compounds are excellent in parenteral administration, but significantly less potent in oral administration.

It is therefore an object of the present invention to provide H ₂ antagonists, optionally containing additional H ₁ antagonist components, which are more effective when administered orally. This object is solved by the preparation of compounds of formula I according to the invention.

In the general formula (I)

R is a group of formula (d) wherein B is -NH- (CH ₂ ) i - or - (CH ₂ ) - where 2.3 or 4, m is 3.4 or 5 - or a group of the general formula (e) - in the formula

D is -CH 2 -S- (CH ₂ ) _n - wherein n is 2 or 3 - or h is

R ⁹ is C 1-3 linear alkyl,

E is -CH ₂ -S- (CH 2) n - where n is 2 or 3 - or R "-A'-B'- is

R 'is phenyl optionally substituted with one or two halogens,

A 'is a bond, -CR ¹ H- group or an N-pyridinyl-imino group,

R 'is phenyl or pyridyl,

B 'is - (CH 2) n' - or -CH 2 -S- (CH ₂ ) _m '- where n' is 1,2,3,4 or 5 and m 'is 2 or 3 - or pyridyl- A group of the formula "-B" - in the formula

A 'represents a bond or N- (mono-halobenzyl) imino,

B "is - (CH ₂ )" - or -CH ₂ -S- (CH ₂ ) m "- in which n" is 2,3 or 4 and m "is 2 or 3 -,

R 'is C 1 -C 6 alkyl or phenyl optionally substituted with phenyl, p is 2 or 3.

In the formula (I), R may have different meanings as listed above.

Preferably, R 'is a (1-6C) alkyl group optionally substituted with phenyl, preferably (1-4C) alkyl. Unsubstituted C1-C4 alkyl groups such as methyl, ethyl, η-propyl, isopropyl, n-butyl and sec-butyl are particularly preferred. p is 2 or 3, preferably 3.

R may be a group of formula (d).

B is -NH- (CH ₂ ) ₁ - or (CH 2) m -, wherein 1 is 2, 3 or 4, m is 3.4 or 5, preferably 4.

R may be a group of formula (e). D is -CH 2 -S- (CH 2) _n - and n is 2 or 3, preferably 2.

R may be a group of formula (h) wherein R ⁹ is a linear C 1 -C 3 alkyl group such as methyl or ethyl, preferably methyl. E is -CH ₂ -S- (CH ₂ ) n - wherein n is 2 or 3, preferably 2.

R may be R "-A'-B'-, wherein R" is phenyl optionally substituted with one or two halogens. When R 'is a substituted phenyl group, the substituent may be a halogen atom in the m or p position, for example fluoro, chloro, bromo or iodo, preferably fluoro or chloro, especially fluoro. A 'is a single bond, -CHR ¹ , or N-pyridylimino. R ¹ is phenyl or pyridyl, B 'is - (CH ₂ ) _n ' - or -CH ₂ -S- (CH ₂ ) _m · -. In these groups, m 'is 2 or 3, n' is 1,2,3,4 or 5.

R may be pyridyl-A "-B" -. A 'is a single bond, N- (monohalobenzyl) imino. When A "is a bond, it is attached to the 2-, 3- or 4-position of the pyridyl ring and B" is attached to the 2-, 3- or 4-position of the pyridyl ring. B "represents (CH ₂ ) n" - or -CH 2 -S- (CH ₂ ) m "- in which m represents 2 or 3 and n" represents 2,3 or 4.

Compounds of formula (I) may be prepared by reacting a compound of formula (II) wherein R and R 'are as defined and L is a leaving group, such as C 1-4 alkylthio, C 1-4 alkoxy. , arylthio, ari50 loxy, preferably methylthio or phenoxy, with a compound of formula (X) wherein X and p are as defined.

The reaction is carried out in equimolar amounts in a polar solvent such as acetonitrile, dimethylsulfoxide, dimethylformamide or pyridine, preferably acetonitrile, at room temperature to the reflux temperature of the solvent used. When L60 is an alkylthio or arylthio group, it is preferable to use an acidic catalyst, for example a catalytic amount of p-toluenesulfonic acid.

The compounds of formula (II) used as starting materials in the process can be prepared from the commercially available leaves by known methods. The

-2HU 201053 Β i

compounds of the formula (Π) in which L is an alkoxy or aryloxy group, for example from an amine of the formula V in which X, p and R are as defined - with a compound of the formula VI - wherein R 'is as defined and L is alkoxy or aryloxy.

Compounds of formula II wherein L is alkylthio or arylthio, such as compounds of formula VIII or VIII wherein R, X and p are as defined and L is alkylthio or arylthio may be prepared by acylation of a compound of formula IX wherein R 'is as defined. The reaction is carried out in the presence of a base such as a tertiary aliphatic amine such as triethylamine or a heterocyclic amine such as pyridine.

The compounds of each method are isolated and purified by known methods, for example by chromatography or recrystallization.

The compounds of the present invention can be formulated into pharmaceutical compositions by any method. The invention further relates to human and veterinary compositions comprising at least one compound of the invention. These compositions may be formulated in conventional manner using one or more carriers and diluents conventionally used in the manufacture of pharmaceuticals.

The compounds of the present invention may be formulated for oral, buccal, topical, parenteral or rectal administration.

Oral formulations are prepared using conventional diluents in the conventional manner. Such formulations may be e.g. tablets, powders, solutions, syrups or suspensions.

Conventionally prepared buccal formulations are used in the form of tablets or leaves.

The compounds of the invention may be administered by parenteral administration in the form of bolus injection or continuous infusion. Injection formulations are prepared in unit dosage form in ampoule or in multiples of unit dose in the form of a preservative.

Suspension, solution, or emulsion formulations may be incorporated into oily or aqueous vehicles, which may optionally contain conventional excipients, e.g. suspending, stabilizing and / or dispersing aids.

In the case of a powder containing the active ingredient, a suitable vehicle, e.g. sterile pyrogen-free water may be formulated for direct use.

The compounds of the present invention may also be formulated for rectal administration. Such compositions are e.g. suppositories and retention enemas, which contain the usual suppository base (e.g., cocoa butter or other glycerides) tar4.

Topical formulations containing the compounds of the invention include creams, gels, lotions, powders, sprays or ointments.

Suitable daily doses of the compounds of the invention in Qrijs preparations are 1-4 doses, totaling 5 mg to 1 g / day, depending on the condition being treated. However, depending on the amount specified in the individual case, depending on the particular properties of the active ingredient. , with respect to the time and periods of dosing, this may be varied. so e.g. it may be necessary in some cases to use less than a pound and in other cases to use a greater amount of active ingredient.

The guanidine carboxylic acid esters of the formula I according to the invention have a cardiotonic action. Compared to prior art similar transdermal compounds (German Patent Laid-open Nos. 35.12.084, 35.28.214, 35.28.215 and European Patent Publication No. 0.199.845), they are surprisingly superior to oral administration and are suitable for cardiac and cardiac administration. treatment and prevention of vascular diseases. They are excellent in a variety of studies, such as having a strong positive inotropic effect on in vivo guinea pigs.

Investigation of hemodynamic properties in an in vivo (anesthetized guinea pig) model

(a) Method

The animals were anesthetized with methane (1.5 g / kg). Volume series for controlled ventilation are tracheal cannulae. Subsequently, both caries were released by surgery, and a tip catheter (3F) was introduced into the right carotid, which was introduced into the left ventricle through the aortic ascendent during continuous pressure recording. Successful penetration of the aortic valve was confirmed by the presence of an atypical left ventricular pressure curve. Through the left carotid we got a throat-thrush? to the aorta for thermodilution measurement. The gas sensor also has a terminal for measuring arterial blood pressure. (The thermoXor sensor is 3F, F. Edwards type). The cold solution (0.2 ml of 0.9% sodium chloride solution, temperature 15 ° C) was catheterized on the right yenugularis before the right atrium. The ECG image was taken in lead 1. The duodenum was exposed by cutting 1 cm long in the median plane of the upper abdomen. Substances to be tested were injected into the duodenum via a needle. The active compounds were suspended in tylose (injection volume 1 ml / kg) and added after hemodynamic stabilization and β-blockade (Metroprolpl 2 mg / kg i.m.).

Circulation parameters were continuously recorded with a direct output device. The contractile capacity (dp / dt) was calculated over the volume pressure curve.

-3HU 201053 Β

6

Spreadsheet

Example Number Dosage Change in contractility mg / kg dp / dt

1. 23 + 50%

2. 23 + 7%

6.5 + 158%

7. 10 + 40%

Comparative Compound 20 + 78%

Reference compound: N ¹ - [3- (imidazol-4-yl) propyl] -N ² - [3- (4-fluorophenyl) -3- (pyridin-2-yl) propyl] guanidine (199,845) Example No. 133 of European Publication No. 15).

Example 1

N- [3- (Imidazol-4-yl) -propyl] -N ² - [4- (pyridin-2-yl) -butyl] -N ³ - (meta-carbonyl) -guanidine (1) / production

a) Preparation of N ¹ - [4- (pyridin-2-yl) butyl] -N ² - (methoxycarbonyl) -S-methylisothiourea

A solution of 3.0 g (83 mmol) of N- [4- (pyridin-2-yl) butyl] -S-methylisothiouronium iodide in 30 mL of dichloromethane was carefully cooled to -15 ° C with 2.4 mL (17.1 mmol) in triethylamine. While cooling, 0.66 ml (83 mmol) of methyl formic acid chloroformate was added dropwise to 20 ml of dichloromethane while maintaining the internal temperature at -15 ° C. The resulting reaction mixture was stirred at this temperature for 1 hour, then allowed to warm to room temperature and stirred for 20 hours. The resulting solution was washed with water (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product obtained is chromatographed on silica gel with dichloromethane / acetone (80:20). Concentration in vacuo of the main fraction gave 2.17 g (90%) of a greenish oil. 40

Formula for C13H19N3O2S (281.38)

R f (CH 2 Cl 2 / CH 3 COCH 3 90:10): 0.2

b) Preparation of N ¹ - [3-Clmidazol-4-yl) propyl] -N- [4- (pyridyl 2-yl) butyl] -N- (methoxycarbonyl) guanidine

1.00 g (3.5 mmol) of N, N-pyridine-4-butyl-N ² (methoxycarbonyl) -S-methylisothiourea and 0.44 g (33 mmol) of 3- (imidazol-4-yl) -propyl and refluxed in 30 ml of acetonitrile for 20 hours. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel with ethyl acetate / methanol (80:20). 0.43 g (34%) of the title compound is obtained as a colorless oil.

C18H26N6O2 (358.45) 55

Rf (CH3COOC2H5 / CH3OH 60:40): 0.4 ¹ H NMR (CD3OD, TMS Internal Standard): δ = 1.4-2.1 (m)

6H, from 23 to 2.9 (m) 4H, 3.1-3.4 (m> 4H. 3.6 (s) 3H, 5.3 (br), 3H, exchangeable with D ₂ O, 6.8 (s) 1H, 7.1-60

7.8 (m) 3H, 7.6 (s) 1H, 8.4 (d) 1H ppm.

Example 2

N- [3- (Imidazol-4-yl) -propyl] -N ² - [4- (pyridin-2-yl) -butyl] -N ³ - (ethoxycarbonyl) guanidine / (2) compound / preparation

a) Preparation of N - (Pyridin-2-yl) -butyl] -N-methylcarbonyl-S-methylisothiourea

As described in Example 1a), 7.0 g (20 mmol) of N- [4- (pyridin-2-yl) butyl] -S-methylisothiourinium iodide and 1.9 ml (20 mmol) of chloroformate were added. ethyl ester to prepare the compound of the formula &lt; RTI ID = 0.0 &gt; The crude product was purified on silica gel using dichloromethane / acetone (9: 1) as the eluent to give 4.94 g (84%) of a yellowish oil.

Formula for C14H21N3O2S (295.41)

R f (CH 2 Cl 2 / CH 3 COCH 3 90:10): 0.3

b) Preparation of N- [3- (Imidazol-4-yl) -propyl] -N- [4- (pyridin-2-yl) -butyl] -N-ethoxycarbonyl-guanidine

1.75 g (5.9 mmol) of N - (pyridin-4-yl) -N-butyl] -N ² (ethoxycarbonyl) -S-methylisothiourea and 0.74 g (5.9 mmol) of 3- (imidazole) were added. 4-yl) -propylamine was boiled with p-toluenesulfonic acid (40 mg) in acetonitrile (30 mL) for 16 hours to give an oil which was evaporated in vacuo and chromatographed on silica gel with ethyl acetate / methanol (80:20) as the eluent. Concentration in vacuo gave a colorless oil which crystallized upon trituration with diethyl ether to give 0.81 g (37%) of a colorless crystalline solid, m.p. 92-94 ° C.

Formula for C19H28N6O2 (372.47)

R f (CH 3 COOC 2 H 5 / CH 3 OH 60:40): 0.45 1 H-NMR (CD 3 OD, TMS Internal Standard): δ = 1.25 (t) 3H, 13-2.0 (m) 6H, 2.65 ( t) 2H, 2.8 (t) 2H, 3.1-3.4 (m) 4H, 4.05 (q) 2H, 4.9 (broad) 3H, interchangeable with D ₂ O, 6.8 (s) ) 1H, 7.2-7.9 (m) 3H, 7.6 (s) 1H, 83 (d) 1H ppm.

Example 3

N * [3- (Imidazol-4-yl) -propyl] -N ² - {3- [N-phenyl-N (pyridin-2-yl) -amino] -propyl} -N ³ - (methoxycarbonyl) -guanidine (3)

a) Preparation of N, N-S-N-phenyl-N-pyridin-4-yl-amino] -propyl} -N ² - (methoxycarbonyl) -S-diethylisothiourea g (33 mmol) N- {3- [N- phenyl-N- (pyridin-2-yl) amino] -propyl} -S-methylisothiouronium iodide and 0.27 ml (33 mmol) of methyl formic acid chloroformate were reacted as described in Example 1a)

1.20 g (96%) of the title isothiourea are obtained as a colorless oil.

Formula for C18H22N4O2S (358.46)

R f (CH 2 Cl 2 / CH 3 OH 95: 5): 0.6.

b) N- [3- (Ιπΰ03Ζο1-4-ΐ1) -ρΓορί1ΕΝ- {3- [Ν-εεείί1N- (pyridin-2-yl) -amino] -propyl} -N - (methoxycarbonyl-4HU-201052) ) -glycinine

1.00 g (2.8 mmol) of N ^J - {3- [N-phenyl N- (pyridin-2-yl) amino] propyl} -N ² (methoxycarbonyl) S-methyl isothiourea and 9.35 g (2.8 mmol!) 3-imidazol-4-yl) -propylamine was boiled in 30 ml of acetonitrile for 16 hours. The crude product was purified by chromatography on silica gel eluting with ethyl acetate / methanol (9010). The main fraction was evaporated in vacuo to give 050 g (41%) of a colorless amorphous solid.

Formula: C23H29N ^{7 * * *} O2 (435.53)

R f (CH 3 COOC 2 H 5 / CH 3 OH 60:40): 0.55 1 H NMR (CD 3 OD, TMS Internal Standard): δ = 1.6-2.1 (m) 4H, 2.7 (t) 2H, 3 , 2-35 (m) 4H, 3.65 (s) 3H, 4.05 (t) 2H, 5.0 (broad) 3H, interchangeable with EhO, 6.3-6.8 (m) 2H, 6.85 (s) 1H, 7.2-7.6 (m) 6H, 7.6 (s) 1H, 8.2 (dd) 1H ppm.

Example 4

N- [3- (Imidazol-4-yl) -propyl] -N ^{2 -} [4- (pyridin-2-ylamino) -butyl] -N ³ - (ethoxycarbonyl) guanidine / Compound (4) / production

a) Preparation of N- [4- (pyridin-2-ylamino) butyl] -N ² - (stoxy-carboxyl) -S-methylisothiourea

As described in Example 1a), 2.01 g (5.5 mmol) of N- [4- (pyridin-2-ylamino) butyl] -S-methylisothiouronium iodide and 0.52 ml (5, Ethyl chloroformate (5 mmol) afforded 1.21 g (71%) of the title compound as a pale yellow oil which solidified in a refrigerator.

Molecular formula: ^C14 H22N4O2S (310.42)

R f (CH 2 Cl 2 / CH 3 OH 90:10): 0.6

b) N ¹ - [3- (imidazol-4-yl) -propyl] -N 2 - [4- (pyridine)

Preparation of 2-ylamino) butyl] -N ³ - (ethoxycarbonyl) guaridine.

1.21 g (3.9 mmol) of N * - [4- (pyridin-2-ylamino) -butyl] -N- (ethoxyl-cabonyl) -S-methyl; -isothiourea, 0.48 g. (3.9 mmol) of 3- (imidazol-4-yl) -propylamine and 40 mg of p-toluenesulfonic acid in 30 ml of acetonitrile were heated for 14 hours. The crude product was purified by chromatography on silica gel using ethyl acetate / methanol (90:10 → 80:20) as the eluent to give 0.81 g (53%) of a beige amorphous solid.

C ^{19 *} H ₂ ⁹ N ⁷ O ₂ (387.49)

Rf (CH3COOC2H5 / CH3OH 60:40): 0.5 ¹ H NMR (CD3OD, TMS Internal Standard): δ - 1.25 (t) 3H,

1.6-2.1 (m) 6H, 2.7 (t) 2H, 3.1-3.5 (m) 6H, 4.15 (q) 2H, 5.0 (broad) 4H, interchangeable D ₂ O, 6.5-6.7 (m) 2H, 6.95 (s) H, 7.4 to 7.6 (m) IH; 7.8 (s) IH; 8.0 (dd ) 1H ppm.

Example 5

N ^{1 -} [3- (Imidazol-4-yl) -propyl] -N ² - [3- (4-fluorophenyl-3- (pyridin-2-yl) -propyl] -N ³ - (methoxycarbonyl) preparation of guanidine / compound of formula (5)

a) Preparation of N ¹ - [3- (4-fluorophenyl) -3- (pyridin-2-yl) propyl] -N-methoxycarbonyl-S-methylisothiocarbanide

As in Example 1a), 8.6 (20 mmol) of N- [3- (4-fluorophenyl) -3- (pyridin-2-yl) propyl] -S-methylisothiouronium iodide and The title compound is obtained from 55 ml (20 mmol) methyl chloroformate. 6.5 g (90%) of a colorless oil are obtained.

Formula for C18H2FN3O2S (361.44)

Rf (90/10 CH2Cl2'CH ₃ COCH 3): 0.5

b) Preparation of N, N-p -imidazol-3-yl-propyl-N- [3- (4-fluorophenyl) -3- (pyridin-2-yl) -propyl] -N ³ - (mesoxycarbonyl) -guanidine in ml of acetolytryl 1 , 34 g (3.7 mmol) of N ¹ - [3- (4-fluorophenyl) -3 (pyridine 2 U) -propyl] -N ² (methoxycarbonyl) -S-methylisothiourea and 0.46 g (3.7 mmol) 3- (imidazol-4-yl) -propylamine is boiled with 30 mg of p-toluenesulfonic acid for 14 hours. The solvent was evaporated in vacuo and the residue chromatographed on silica gel using ethyl acetate / methanol (90:10) as eluent. Concentration in vacuo of the main fraction afforded 0.91 g (56%) of a colorless amorphous solid.

Formula for C23H27FN6O2 (438.51)

R f (CH 3 COOC 2 H 5 / CH 3 OH 60:40): 0.44 1 H-NMR (CD3OD TMS internal standard): δ = 1.7-2.1 (quintet) 2H, 2> 2.8 (m) 4H, 3 , 1-3.5 (m) 4H, 3.7 (s) 3H, 4.25 (t) 1H, 5.3 (broad) 3H, interchangeable with D2O, 6.9-7.9 (m) 9H, 8.6 (dd) 1H ppm.

Example 6

N- [3- (Imidazole-4-yl) -propyl] -N ² - [3- (4-fluorophenyl) -3- (pyridin-2-yl) -propyl] -N ³ - (ethoxycarbonyl) guanidine / Preparation of compound (6)

a) ^{Preparation of} N ¹ - (3- ^{, 4} -F ^1. UGr main) -3- (pyridin-2-yl) -propyl] -N ² - (ethoxycarbenyl) -O-phenylisocarbamide

1.40 g (4.9 mmol) of diphenyl ester of N-ethoxycarbonylimidosenoic acid in 20 ml of tetrahydrofuran were cooled to + 5 ° C. While cooling, 1.13 g (4.9 mmol) of 3- (4-fluorophenyl) -3- (pyridin-2-yl) propylamine in 20 ml of tetrahydrofuran are added dropwise over 15 minutes. The resulting reaction mixture was stirred at room temperature for 4 hours and then evaporated in vacuo. The colorless oil thus obtained was further purified without purification.

Formula for C24H24FN3O3 (421.47)

R f (CH 2 Cl 2 / CH 3 OH 95: 5): 0.7

b) N ¹ - [3- (Imidazol-4-yl) -propyl] -N ² - [3- (4-fluorophenyl) -3- (pyridin-2-yl) -propyl] -N- (ethoxycarbonyl) guanidine production

Crude N- [3- (4-fluorophenyl) -3- (pyridin-2-yl) ^{propyl-N'-i-O-ethoxycarbonyl-fenilizotiokarbamidnak} in 40 ml of acetonitrile 2.06 g (4.9 mmol) To this solution was added 0.61 g (4.9 mmol) of 3- (imidazol-4-yl) -propylamine and the reaction mixture was refluxed for 7 hours. The solvent was evaporated in vacuo and the oily residue was chromatographed on silica gel using ethyl acetate / methanol (80:20) as the eluent. Concentration of the main fraction in vacuo gave 0.99 g (45%) of a colorless oil.

Formula for C24H29FN6O2 (452.53)

R f (CH 3 COOC 2 H 5 / CH 3 OH 60:40): 0.6 ^{x 1} H-NMR (CD 3 OD, TMS internal standard): δ = 1.2 (t) 3H,

1.7-2.1 (quintet) 2H, 2.2-2.8 (m) 4H, 3.1-3.5 (m) 4H, 4.1 (q) 2H, 4.2 (t) 1H, 4.9 (b) 3H, interchangeable with D ₂ O, 6.8-7.9 (m) 9H, 8.55 (dd) 1H ppm.

-5HU 201053 Β

Example 7

N- [3- (Imidazol-4-yl) -propyl] -N ² - [3- (4-fluorophenyl) -3- (pyridin-2-yl) -propyl] -N ³ - (butoxycarbonyl) ) guanidine (7)

a) Preparation of N ¹ - [3- (4-Fluorophenyl) -3- (pyridin-2-yl) -propyl] -N- (butOM-carbonyl) -O-phenylisourea

In analogy to Example 6a, 3.13 g (10 mmol) of N-butoxycarbonylimidazole diphenyl ester and 230 g (10 mmol) of 3- (4-fluorophenyl) -3- ( from pyridin-2-yl) -propylamine in tetrahydrofuran to give the title compound. The crude product is not isolated and further converted into solution.

Formula for C26H28FN3O3 (449.52)

R f (CH 2 Cl 2 / CH 3 OH 95: 5): 0.85

b) N- [3- (Imidazol-4-yl) -propyl] -N- [3- (4-fluorophenyl) -3- (pyridin-2-yl) -propyl] -N ³ - (butoxycarbonyl) - preparation of guanidine

3- (Imidazol-4-yl) -nropylamine (1.25 g, 10 mmol) was added to crude N- [3- (4-fluorophenyl) -3- (pyridin-2-yl) 4.49 g (10 mmol). ) -propyl] -N ² - (butoxycarbonyl) -O-phenylisocarbamide in 60 ml tetrahydrofuran and the reaction mixture was refluxed for 8 hours. After evaporation of the solvent in vacuo, the oil is chromatographed on silica gel using ethyl acetate / methanol (80:20) as the eluent. so

1.40 g (29%) of a colorless amorphous solid were obtained as the main fraction.

Formula for C26H33FN6O2 (480.59)

Rf (CH3COOC2H5 / CH3OH 60/40): 0.65 ¹ H-NMR data (CD3 OD, TMS internal standard): δ = 0.95 (t) 3H,

1.1-2.9 (m) 10H, 3.2-3.8 (m) 4H, 4.0-4.3 (2t) 3H, 6.9-7.8 (m) 9H, 8, 7 (d) 1H; 9.3 (broad) 1H, exchangeable with EbO, 10.6 (broad) 1H, exchangeable with d ₂ O ppm.

& example

N- [3- (Imidazol-4-yl) -propyl] -N- [3- (4-fluorophenyl) -3- (pyridin-2-yl) -propyl] -N ³ - (phenoxycarbonyl) guanidine (8)

a) Preparation of N ¹ - [3- (4-fluorophenyl) -3- (pyridin-2-yl) propyl] -N- (phenoxycarbonyl) -O-phenylisourea

As described in Example 6a), 3.33 g (10 mmol) of N- (phenoxycarbonyl) imidocarbonic acid diphenyl ester and 23O g (10 mmol) of 3- (4-fluorophenyl) -3- (pyridin-2-yl) -propylamine in 60 ml of acetonitrile to give the title compound. After stirring at room temperature for 5 hours, the compound is further reacted in solution without isolation.

Formula: C28H24FN3O3 (469.51)

b) N ¹ - [3- (Imidazol-4-yl) -propyl] -N ² - [3- (4-fluorophenyl) -3- (pyridin-2-yl) -propyl] -N ³ - (phenoxycarbonyl) ) -guanidine

4.69 g (10 mmol) of N ¹ - [3- (4-fluorophenyl) -3- (pyridin-2-yl) propyl] -N ² (phenoxycarbonyl) obtained according to Example 8a are obtained. A solution of o-phenylisocarbamide in acetonitrile was mixed with 1.25 g (10 mmol) of 3- (imidazol-4-yl) propylamine and refluxed for 6 hours. The crude product obtained is chromatographed on silica gel with ethyl acetate / methanol (80:20). The main fraction gave 3.65 g (73%) of a colorless amorphous solid.

Molecular Formula CísH ^ FNóOz (59037)

R f (CH 3 COOC ² H 5 / CH 3 OH 80:20): 9.6 ¹ H NMR (CD3OD, TMS internal standard): δ - 1.7 (quintet) 2H, 2.1 - 2.6 (m) 4H, 2 , 8-33 (m) 4H, 43 (t) 1H,

6.7-7.9 (m) 15H, 1H, exchangeable with EHO, 8.7 (dd) 1, 93 (t) 1 H, exchangeable with D ₂ O ppm incl.

Example 9

N- [3- (Imidazol-4-yl) -propyl] -N ² - [3- (4-fluorophenyl) -3- (pyridin-2-yl) -propyl] -N ³ - (benzyloxy) -carbonyl) guanidine (9)

a) Preparation of N- [3- (4-fluorophenyl) -3- (pyridin-2-yl) propyl] -N- (benzyloxycarbonyl) -S-methylisothiocarbainide

As described in Example 1a), 2.16 g (5 mmol) of N- [3- (4-fluorophenyl) -3- (pyridin-2-yl) propyl] -S-methylisothiouronium iodide and After chromatography on silica gel (72 mL, 5 mmol) using dichloromethane / acetone (95: 5) as silica gel, the title compound was obtained as a pale yellow oil.

Yield: 135 g (71%)

Cumulative Formula: C24H24FN3O2S (43734)

R f (CH 2 Cl 2 / CH 3 COCH 3 95: 5): 0.7

b) N ¹ - [3- (Imidazol-4-yl) -propyl] -N ² - [3- (4-fluorophenyl) -3- (pyridin-2-yl) -propyl] -N ³ - (benzyl); preparation of oxycarbonyl) guanidine

1/23 g (2.8 mmol) of N ¹ - [3- (4-fluorophenyl) -3- (pyridin-2-yl) propyl] -N- (benzyloxycarbonyl) -S-methylisothiourea and 035 g (2.8 mmol) of 3- (imidazol-4-yl) -propylamine in 25 ml of acetonitrile was refluxed for 24 hours. After purification by chromatography and evaporation of the solvent in vacuo, the crude product was purified on silica gel using ethyl acetate / methanol (80:20) as the eluent to give 038 g (40%) of a colorless amorphous solid.

Formula for C29H31FN6O2 (514.60)

R f (CH 3 COOC 2 H 5 / CH 3 OH 80:20): 03

1 H NMR (CD 3 OD, TMS Internal Standard): δ - 1.7-2.9 (m) 6H, 3.1-3.7 (m) 4H, 4.1-43 (m) 1 H, δ / 2 (s) 2H, 6.85 (s) 1H, 6.9-7.8 (m) 14H, 1H exchangeable with D ₂ O,

8.7 (dd) 1, 93 (br), 1H, exchangeable with D ₂ O ppm incl.

Example 10

N ¹ - [3- (Imidazol-4-yl) -propyl] -N ² - {2- [N- (4-chlorobenzyl) -N- (pyridin-2-yl) amino] ethyl} -N ³ (ethoxycarbonyl) guanidine (10)

a) Preparation of N ¹ - {2TN- (4-chlorobenzyl) -N- (pyridin-2-yl) amino] ethyl} -N ⁷ - (ethoxycarbonyl) -S-methylisothiourea in Example 1a) 1.50 g (3.2 mmol) of N- {2- [N- (4-chlorobenzoyl) -N- (pyridine-2-U) -amino] ethyl] -5-methylisothioeuronium iodide, and The title compound was prepared from 031 ml (3.2 mmol) of ethyl chloroformate. 1.20 g (91%) of product are obtained as a colorless oil.

Formula for C19H23CIN4O2S (406.93)

R f (CH 2 Cl 2 / CH 3 COCH 3 99: 1): 0.4

b) N ¹ - [3- (Imidazol-4-yl) -propyl] -N ² - {2-N - (4-chlorobenzyl) -N- (pyridin-2-yl) -amino] -ethyl} -N ³ Preparation of (ethoxycarbonyl) guanidine

-6HU 201053 Β

1.02 g (2.5 mmol) of N ^{1 -} [24 N (4-chlorobenzyl) · · · · (pyridin-2-yl) amino] ethyl} - N ² - (ethoxycarbonyl) -S-methyl -isothiourea and 0.31 g (2.5 mmol) of 3- (imidazol-4-yl) -propylamine in 20 ml of acetonitrile are refluxed for 24 hours. The crude product obtained is purified by column chromatography on silica gel using ethyl acetate / methanol (80:20) as the eluent. The main fraction was evaporated in vacuo to give a colorless oil which was crystallized with 5 mL of ethyl acetate / methanol (80:20). 0.42 g (35%) of colorless crystals were obtained, m.p. 94-96 ° C.

Formula Formula: C24H30CIN702 (484.00)

R f (CH ₃ COOC ₂ H ₅ / CH ₃ OH _/ conc. NH ₄ OH 80: 15: 5): 0.55

1 H-NMR (CD3OD, TMS internal standard): δ = 1.25 (t) 3H.

1.9 (quintet) 2H, 2.7 (t) 2H, 3.2-3.9 (m) 6H, 4.1 (qj 2H, 4.8 (s) 2H, 4.9 (broad) 3H , interchangeable with D ₂ Oval, 6.6-6.9 (m) 3H, 7.2-7.7 (m) 6H, 8.2 (dd) 1H ppm.

II. example

N ¹ - [3- (imidazel-4-yl) propyl] -N ² - {[5-methylimidazol-4-yl) methyl] thio} ethyl N ³ - (ethoxycarbonyl) - guanidine (II)

a) Preparation of N 4 -phenylmethyl-imidazol-H-yl] methyl] thio] ethyl N ² - (ethoxycarbonyl) -S-methylisothiourea

7.8 g (20.9 mmol) of N - {[5-methylimidazol-4-yl) methyl] thio} ethyl-5-methylisothiouronium iodide, as described in Example 1a), 4.0 ml. (41.8 mmol) of ethyl chloroformate and 8.7 mL (62.7 mmol) of triethylamine. After extraction and evaporation of the organic phase, the crude product is chromatographed on silica gel with dichloromethane / acetone (90:10). Concentration of the main fraction (55%) gave almost crystalline material, m.p. 75-76 ° C.

Formula: C15H24N4O4S2 (388.51)

R f (CH 2 Cl 2 / CH 3 COCH 3 90:10): 0.4

b) Preparation of N, N-p-O-dimethyl-4-yl-propyl-N '- (N-methyl-imidazol-4-yl) -methyl] -thio} -ethyl-N- (ethoxycarbonyl) -guanidine

N - {[5-methylimidazol-4-yl) methyl] thio} ethyl-N ² (ethoxycarbonyl) -S-methylisothiourea and 1.3 g (103 mmol) of 3- (imidazole). -4-yl) -propylamine with 0.1 g ptoluenesulfonic acid in 100 ml acetonitrile was refluxed for 16 hours. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel using ethyl acetate / methanol (60:40) as the eluent.

Concentration in vacuo of the polar main fraction gave 1.1 g (27%) of a colorless amorphous solid.

Cumulative Formula: C17H27N7O2S (39331)

R f (CH 2 Cl 2 / CH 3 COCH 3 60:40): 0.5 ^{X 1} H NMR (CD3OD, TMS Internal Standard): δ = 1.2 (t) 3H

1.9 (quintet) 2H, 2.2 (s) 3H, 2.7 (t) 4H, 3.2-3.6 (m) 4H, 3.8 (s) 2H, 4.1 (q) 2H, 5.2 (broad) 4H, interchangeable with D ₂ O, 6.9 (s) 1H, 7.6 (s) 1H, 7.7 (s) 1H ppm.

Example 12

N- [3- (3,4-Dichlorophenyl) -3- (pyridin-2-yl) -propyl] -N ² (ethoxycarbonyl) -N ³ · [3- (1H-imidazole-4-yl) -N il) Preparation of piopilylgiamdm (12)

1.41 g (5 mmol) of 3- (3,4-dichlorophenyl) -3- (pyridin-2-yl) propylamine and 1.43 g (5 mmol) of N- (ethoxycarbonyl) diphenyl- imidocarbonate in 20 ml of acetonitrile was stirred for 20 minutes at room temperature. Addition of 0.65 g (5.2 mmol) of pH 1'Itidazol-4-yl) -propylamine hrs the reaction mixture is refluxed for 10 hours, then the reaction mixture is concentrated in vacuo and the residue is treated with 5% hydrochloric acid solution and then extracted with diethyl ether. After basification with ammonia, the reaction mixture is extracted with methylene chloride, the organic phase is washed with water, dried over sodium sulfate and concentrated in vacuo. The product obtained is isolated by chromatography on a Kieselgel 60 PF 2 column containing gypsum (eluent: chloroform / methanol 993/03 ammonia). The solid obtained after evaporation of the eluate (1.4 g, 56%) was crystallized from ethyl acetate / diethyl ether, m.p. 73-75 ° C.

Elemental analysis for C24H28Cl2N6O2 (503.4):

calculated. C, 57.26; H, 5.61; N, 16.69; Found: C, 57.04; H, 5.78; N, 16.29.

Mass Spectrum (FAB Method): m / z (rel. Int [%] = 503 ([M + H]), 9), 264 (73), 109 (100), 95 (3U).

Λ NMR (CD3OD, TMS Internal Standard): δ = 1.13 (t) 3H,

1.75 (m) 2H, 2.25 (m) 1H, 2.43 (m) 1H, 23 (m, partially covered) 2H, 3.10 (m) 2H, 3.16 (m) 2H, 3 88 (q) 2H; 4.20 0), 1H, 6.6-7.2 (br), 2H, 1H exchangeable with _D2 O, 7.23 (m) 1H, 735 to 7.8 (m ) 6 H 834 (d) 1Η, S, 9 (br), 1H, exchangeable with d ₂ O, 11.8 (br), 1H, exchangeable with d ₂ O, ppm.

Example 13

N ¹ - [3- (3,4-Difluoro-phenyl) -3- (pyridin-2-yl) -propyl] -N- (etorocarbonyl) -N ³ - [3- (1H-imidazol-4-yl) ), propyl-guanidine (13)

The compound of dm was prepared as described in Example 12 with 3- (3,4-difluorophenyl) -3- (pyridin-2-yl) propylamine (1.24 g, 5 mmol). Yield:

1.2 g (51%) of colorless crystals, m.p. 119-120 ° C (ethyl acetate / ether).

Elemental Analysis for: C ^ HH ^ ChNNClh (4703) Calculated: C: 61.27; H: 6.00; N: 17.86 Found: C: 61.14; H: 6.22; N: 1737%.

Mass Spectrum (FAB Method): m / z (rel. Int [%] = 471 ([M + H]), 8), 425 (4), 323 (100), 204 (19), 109 (69), 95 (15), 81 (25).

1 H NMR (d 6 -DMSO, TMS Internal Standard): δ = 1.13 (t) 3H, 1.75 (m) 2H, 2.24 (m) 1 H, 2.44 (m) 1 H, 23 (m, partially covered) 2H, 3.08 (m) 2H, 3.17 (m) 2H, 3.88 (q) 2H, 4.18 (t) 1H, 6.6-7.2 (broad) 2H, 1H interchangeable with D ₂ O 7.2-7.6 (m) 6H, 7.71 (m) 1H, 8.54 (d) 1H, 8.9 (broad) 1H, interchangeable with EbO, 11.8 (broad) 1H, exchangeable with D ₂ O, ppm.

Example 14

NM3- (3,5-Difluoro-phenyl) -3- (pyridin-2-yl) propyl] -N- (ETT-carbon is zd '', N ³ - [3- (lH-imidazol-4-yl ) 7

-7H «J 201053 Β • opylj-guamdin (compound of formula (14))

The title compound was prepared as described in Example 12 from 1.24 g (5 mmol) of 3- (33-difluorophenyl) -3- (pyridin-2-yl) propylamine. Yield:

Colorless crystals (1.3 g, 55%), m.p. 104-105 ° C (ethyl acetate / ether).

Elemental analysis for C24H28F2N6O2 (470.5):

Found: C, 61.27; H, 6.00; N, 17.86; Found: C, 60.95; H, 6.08; N, 17.63.

Mass Spectrum (FAB Method): m / z (rel. Int [%] = 471 ([M + H]), 9), 232 (100), 204 (17), 172 (11), 109 (66), 95 (15).

1 H NMR (d 6 -DMSO, TMS Internal Standard): δ = 1.13 (t) 3H, 1.76 (m) 2H, 2.2-2.6 (m) 4H, 3.10 (m) 2H, 3.16 (m) 2H, 3.91 (q) 2H, 4.21 (t) 1H, 6.77 (broad) 1H, interchangeable with IhO, 7.0-7.45 (m) 5H, 7.50 (s) 1H, 7.71 (m) 1H, 8.55 (d) 1H, 8.9 (broad) 1H, interchangeable with D2O, 11.85 (broad) 1H, interchangeable with D2O, ppm.

Example 15

N ¹ - [3- (4-fluorophenyl) -3- (pyridin-2-yl) propyl] -N ² (ethoxycarbonyl) -N ³ - [3- (1H-imidazol-4-yl) -propyl] guanidine (15)

The title compound was prepared as described in Example 12 from 1.15 g (5 mmol) of 3- (4-fluorophenyl) 3- (pyridin-3-yl) propylamine. Yield: 1.15 g (47%) of colorless crystals, m.p. 104-105 ° C (ethyl acetate / ether).

Elemental analysis for C24H29FN6O2 (452.5):

Found: C, 63.70; H, 6.46; N, 18.57; Found: C, 63.33; H, 6.65; N, 18.39.

1 H-NMR (d 6 -DMSO, TMS Internal Standard): δ = 1.13 (t) 3H, 1.75 (m) 2H, 2.29 (m) 2H, 2.5 (m, partially covered) 2H, 3.09 (m) 2H, 3.16 (m) 2H, 3.88 (q) 2H, 4.08 (t) 1H, 6.77 (broad) 1H, 7.0 (very broad) 1H , interchangeable with D ₂ O, 7.12 (dd) 2H, 7.30 (dd) 1H, 7.40 (dd) 2H, 730 (s) 1H, 7.77 (d) 1H, 8.40 ( d) 1H, 8.56 (s) 1H, 8.95 (broad) 1H, interchangeable with D ₂ O, 18.4 (broad) 1H, interchangeable with D ₂ O, ppm.

Example 16

N ¹ - [(1,1-Dimethylethyl) oxycarbonyl] -N ² - [3- (4-fluorophenyl) -3- (pyridin-2-yl) propyl] -N ³ - [3- ( 1H-imidazol-4-yl) -propyl] -guanidine (16)

The title compound was prepared as described in Example 12 from 1.15 g (5 mmol) of N- (tert-butoxycarbonyl) diphenylimidocarbonate and 0.65 g (5.2 mmol) of 3- (1H-imidazole). -4-yl) propylamine. Yield: 1.1 g (46%) of colorless crystals, m.p. 116-117 ° C (ethyl acetate / ether).

Elemental analysis for C26H33FN6O2 (480.6):

Found: C, 64.98; H, 6.92; N, 17.49. Found: C, 65.01; H, 7.17; N, 17.56.

Mass Spectrum (FAB Method): m / z (rel. Int [%] = 481 ([M + H] +), 6), 381 (39), 214 (100), 186 (29), 151 (12), 109 (90), 100 (45), 95 (22), 82 (31), 81 (39), 57 (88).

1 H NMR (d 6 -DMSO, TMS internal standard): δ 1.37 (s) 9H, 1.74 (m) 2H, 231 (m) 1H, 235-2.6 (a) 3H, 3 , 06 (m) 2H, 3.17 (m) 2H, 4.17 (t) 1H, 6.76 (s) 1H, 6.9 (broad) 1H, interchangeable with D2O, 7.10 (dd) 2H, 7.20 (dd) 1H, 732 (d) 1H, 7.40 (dd) 2H, 7.49 (s) 1H,

7.69 (dd) 1H, 833 (d) 1H, 8.9 (broad) 1H, interchangeable with D2O, 11.9 (broad) 1H, interchangeable with D2O, ppm.

Example 17 ^ - (Etpxi-carbonyl-N ² - [3- (lH-imidazol-4-yl) propyl] -N ³ - [2-phenyl-2- (2-pyridyl) ethyl] guanidine / ( 17)

A12. The title compound was prepared from 0.99 g (5 mmol) of 2-phenyl-2- (2-pyridyl) ethylamine.

Yield: 0.6 g (27%) of colorless crystals, m.p. 145 DEG C. (ethyl acetate / ethanol).

Cumulative Formula: C23H28N6O2 (4203)

Mass Spectrum (FAB Method): m / z (rel. Int [%] = 421 ([M + H]), 13), 394 (6), 375 (8), 182 (100), 180 (38), 169 (25), 168 (21), 162 (29), 109 (65), 95 (10), 81 (25).

1 H NMR (d 36 -DMSO, TMS Internal Standard): δ = 1.11 (m) 3H, 1.67 (m) 2H, 2.45 (m) 2H, 3.0-4.05 (broad ) 6H,

4.45 (broad) 1H, 6.73 (s) 1H, 7.1 (broad) 1H, interchangeable with D2O, 7.15-7.45 (m) 7H, 7/50 (s) 1H, , 70 (m) 1H, 8.55 (m) 1H, 8.90 (broad) 1H, interchangeable with O2O, 13.43 (broad) 1H, interchangeable with U20, ppm.

18példa ^ - (Ethoxy-carbonyl-N ² - [3- (4-fluorophenyl) -3-phenylpropyl] -N ³ - [3- (lH-imidazol-4-yl) propyl] guanidine / Preparation of compound (18)

The title compound was prepared as described in Example 12 from 1.15 g (5 mmol) of 3- (4-fluorophenyl) 3-phenylpropylamine. Yield: 1.1 g (49%) of a colorless crystalline solid, m.p. 131 DEG C. (ethyl acetate / ether).

Elemental analysis for C25H30FN5O2 (451.5):

Found: C, 66.50; H, 6.70; N, 15.51; Found: C, 66.32; H, 6.87; N, 1531.

Mass Spectrum (FAB Method): m / z (rel. Int [%] = 452 ([M + H]), 6), 406 (4), 185 (20), 109 (100), 95 (18), 91 (20).

1 H-NMR (d 6 -DMSO, TMS Internal Standard): δ = 1.13 (t) 3H, 1.75 (m) 2H, 2.2-235 (m) 2H, 23 (m, partially covered) 2H, 3.08 (m) 2H, 3.17 (m) 2H, 3.89 (q) 2H, 4.01 (t) 1H, 6.6-7.1 (broad) 2H, 1H interchangeable with D2O- val, 7.1-7.4 (m) 9H, 7.49 (s) 1H, 8.9 (broad) 1H, interchangeable with IhO, 11.8 (broad) 1H, interchangeable with D2O, ppm.

Example 19

Preparation of N ¹ - (33-Diphenylpropyl) -N ² - (etaacarbonyl) -N ^{3 -} [(1H-imidazol-4-yl) propyl] guanidine (19)

The title compound was prepared as described in Example 1 from 2.06 g (5 mmol) of N- (33-diphenylpropyl) -S-methylisothiouronium iodide. A solution of the N, N-bis-S-diphenylpropyl-N ² -8 (ethoxymethyldis-D-methylthiothiothiocatharide) prepared in Example 1a) is washed with water and dried over sodium sulfate and concentrated in vacuo. and the residue was taken up in 20 ml of acetonitrile, 0.65 g (5.2 mmol) of 3- (1H-imidazole)

After addition of 4-yl) -propylamine, the reaction mixture was refluxed for 20 hours. The product was isolated by chromatography on a Kieselgel 60 PF2S4 gypsum column (eluent: chloroform / ethanol 98: 2, ammonia). Concentration of the eluate gave a solid (0.9 g, 42%) which was crystallized from ethyl acetate / diethyl ether to give colorless crystals, m.p. 125-126 ° C.

Elemental analysis for C25H21N5O2 (433.6):

Found: C, 69.26; H, 7.21; N, 16.15; Found: C, 69.30; H, 7.43; N, 16.24.

1 H-NMR (d 6 -DMSO, TMS Internal Standard): δ = 1.13 (t) 3H, 1.75 (m) 2H, 2.28 (m) 2H, 23 (m, partially covered) 2H, 3.09 (m) 2H, 3.17 (m) 2H, 3.89 (q) 2 - 3.99 (t) 1H, 6.76 (broad) 1H, 7.0 (windy) 1H, exchangeable EhO- val, 7.1-735 (m) 10H, 7.49 (s) 1H _; 8.95 (wide) IH, interchangeable with D2O,! 1.9 (wide) IR can be replaced with IhO, ppm.

Example 20

N ¹ - (Ethoxycarbonyl) N ² - [3- (1H-imidazol-4-yl) propyl] -N- {2 - [(pyridin-2-yl) methyl] ethyl} guanidine / Preparation of compound (20)

A19. The title compound was prepared from 1.85 g (5 mmol) of N- [2 - [(pyridin-2-yl) methylthio] ethyl} -S-methyl isothiouronium iodide. Yield: 1.3 g (54%) of a colorless crystalline solid, m.p. 60-61 C (ethyl acetate / diethyl ether).

Elemental analysis based on C> §H2f FemaleOjS (390.5):

Found: C, 5536; H, 6.71; N, 21.52. Found: C, 5537; H, 7.01; N, 21.23.

1 H NMR (d 6 -DMSO, TMS Internal Standard): δ = 1.14 (t) 3H, 1.77 (m) 2H, 231 (m) 2H, 2.62 (m) 2H, 3.19 (m) 2H, 338 (m) 2H, 3.84 (s) 2H, 3.93 (q) 2H, 6.77 (s)

IH, 7.2 (very wide) IH, interchangeable with D2O,

7.26 (dd) 1H, 7.44 (d) 1H, 733 (s) 1H, 7.75 (dd) 1H,

8.48 (d) IH, 9.0 (wide) IH, interchangeable with D ₂ O,

II, 8 (broad) 1H, exchangeable D2O-V2I, ppm.

Example 21

N ¹ - (Ethoxycarbonyl) -N- [3- (1H-imidazol-4-yl) propyl] -N - {2 - [(pyridin-3-yl) methylthio] ethyl} guanidine / Preparation of compound (21)

A19. The title compound was prepared from 1.85 g (5 mmol) of N- {2 - [(pyridin-3-yl) methylthio] ethyl} -S-methylisothiouronium iodide. Yield: 1 (2 g, 50%) as colorless crystals, m.p. 90-91 ° C (ethyl acetate / diethyl ether).

Elemental analysis for C28H20N6O23 (3903):

Found: C, 5536; H, 6.71; N, 2132; Found: C, 5538; H, 6.93; N, 21.45.

1 H-NMR (d 6 -DMSO, TMS Internal Standard): δ = 1.15 (t)

III. 1.78 (IB) 2H, 23-2.65 (ml 4H), 3.17 (m) 2H 338 <2H. 3.80 U) 211.3.93 (q) 2H, 6.78 (broad)

IH, 73 (naguw wide) IH, interchangeable with 020, 734 (dd) IH, 733 (s) IH, 7.79 (d) IH, 8.45 (d) IH, 834 also) 1H, 7, 95 (wide) UH, interchangeable with DIO,

II, 85 (broad) 1H, interchangeable with DX1, ppm.

2Zp?> 4í ^!

N ^! Preparation of - (Ftpx.c.) N ^{2 -} [3- (1H-imidazol-4-U) propyl] -N'-phenylphenylthio) ethyl] guanidine (22).

The title compound was prepared as described in Example 12 from 0.84 g (5 mmol) of 2- (phenylmethylthio) ethylamine. Yield: 1.0 g (51%) of colorless crystals, m.p. 91-92 ° C (ethyl acetate / diethyl ether).

Elemental analysis for C19H27N5O2S (3893):

Found: C, 58.59; H, 6.99; N, 17.98; Found: C, 58.29; H, 7.00; N, 17.83.

Mass Spectrum (FAB Method): m / z (rel. Int)%] = 309 ([M + H]), 23), 344 (11), 172 (9), 151 (10), 1091 <P), 95 (11), 91 (100).

1 H NMR (d 6 DMSO, TMS Internal Standard): δ-1.15 (t) 3H, 1.76 (m) 2H. 2.5-235 (tn, partly covered) 4H,

3.18 (m) 2H, 3.37 (m) 2H, 3.76 (s) 2H, 3.93 (q) 2H,

6.77 (s) HH, 7.0 hiss? <IH, interchangeable with D2O, /, 2-7.4 (m) 5tt,? 33 ('1 IH, 9.0 (wide) 1H, interchangeable with L' .t ', 11.85 (broad) 1H , interchangeable with D ₂ O, ppm

Example 23

N ¹ - {2 - [(2 D'amino-methylene-aminothiazol-4-yl) -methyl-thio] -H}} - H ² - (ethacarbonyl) -N ³ - [3- (1H) Preparation of imidazo-N-propyl-guaGidine (23)

A12. The compound of Example dm was prepared from 1.16 g (5 mmol) of 2 - [(2-diaminomethylene-aminothiazole-1'L) -methyl-thio] -ethylamine. Yield: 1.2 g (53%) of a colorless crystalline material which, after recrystallization from ethyl acetate / ethanol, sintered at 110-114 ° C.

Elemental analysis based on the formula Ci * H27N9O2S2 (453.6):

Found: C, 45.02; H, 6.00; N, 27.79; Found: C, 44.79; H, 6.09; N, 28.07.

Mass Spectrum (FAB Method): m / z (rel. Int [%] = 454 ([M + H]). 10), 408 (8), 211 (18), 155 (100), 113 (29). 109?), 95 (22), 93 (14), 82 (24), 81 (29).

1 H NMR (d 6 -DMSC, TMS Internal Standard): δ = 1.14 (t) 3H, 1.77 (m) 2H, 2.45-2.65 (m) 4H, 3.18 (m) ) 2H, 338 (m) 2H, 3.61 (s) 2H, 3.93 (q) 2H, 636 (s) 1H,

6.77 (s) 1H, 6.84 (broad) 4H, interchangeable with D ₂ O,

7.75 (broad) IH, interchangeable with D ₂ O, 732 (s) IH,

8.95 (wide) 1H is displaceable with D2O, 11.85 (broad) 1H, interchangeable with L1 O, ppm.

Claims (16)

PATENT CLAIMS 1. Process Flavor Guanidine Derivatives of Formula I -? 1 ⁵ pletfc -9HU 201053 Β R is a group of formula (d) wherein B is -NH- (CH ₂ ) i - or - (CH ₂ ) _m - wherein 1 is 2, 3 or 4, m is 3, 4, or 5 - or (e) D is -CH 2 -S- (CH ₂ ) _n - wherein n is 2 or 3 - or h is R ⁹ is C 1-3 linear alkyl, E is -CH ₂ -S- (CH ₂ ) n - wherein n is 2 or 3 - or R "-A'-B'- is R 'is phenyl optionally substituted with one or two halogens, A 'is a bond, -CR'H or N-pyridylimino, R 'is phenyl or pyridyl, B 'is - (CH ₂ ) _n ' - or -CH ₂ -S- (CH ₂ ) _m '- wherein n' is 1,2,3,4 or 5 and m 'is 2 or 3 - or pyridyl-A "-B" - in the formula A 'represents a bond or N- (mono-halobenzyl) imino, B "is - (CH ₂ )" - or -CH ₂ -S- (CH ₂ ) _m "- in which n" is 2,3 or 4 and m "is 2 or 3 -, R 'is a C 1 -C 6 alkyl group or a phenyl group optionally substituted with phenyl, p is 2 or 3, characterized in that a compound of formula II wherein R and R' are as defined herein and L is reacting a leaving group with a compound of formula III wherein p is as defined herein. (Priority: 08.04.1988) 2. A process for preparing a guanidine derivative of formula (I): wherein: R is a group of formula (d) wherein B is -NH- (CH ₂ ) i - or - (CH ₂ ) _m - wherein 1 is 2, 3 or 4, m is 3, 4, or 5 - or (e) D is -CH 2 -S- (CH ₂ ) _n - in which n is 2 or 3 - or (h) in which R ⁹ is C 1-3 linear alkyl, E is -CH ₂ -S- (CH ₂ ) _n - wherein n is 2 or 3 - or R "-A'-B'- is R 'is phenyl optionally substituted with one or two halogens, A'represents a bond, -CR ¹ !! or N-pyridylimino, R 'is phenyl or pyridyl, B 'is (CH ₂ ) _n or -CH ₂ -S- (CH ₂ ) _m > - wherein n' is 1, '2,3,4 or 5 and m' is 2 or 3 - or pyridyl-A "-B" - in the formula A 'represents a bond or N- (mono-halobenzyl) imino, B "is -CH ₂ ) _n " - or -CH ₂ -S- (CH ₂ ) _m - in the formulas n "is 2,3 or 4 and m" is 2 or 3—, R 'is a C 1 -C 6 alkyl group or a phenyl group optionally substituted with phenyl, p is 2 or 3, characterized in that a compound of formula II wherein R and R * are as defined above and L is a leaving group - a compound of formula (ΠΙ) wherein p is as defined herein. (Priority: August 7, 1987) A process for the preparation of a compound of formula (I) according to claim 2 wherein R is a group of formula (d), B is - (CH ₂ ) s - 4 - or - NH - (CH ₂ ) i -. group - where 1 is 2,3 or 4, R 'is C 1 -C 6 alkyl optionally substituted with phenyl, or phenyl, p is 2 or 3, characterized in that the appropriately substituted starting materials are used. (Priority: August 7, 1987) A process for the preparation of a compound of formula (I) according to claim 2 wherein R is (h ² ), E is -CH ₂ -S- (CH ₂ ) ₂ -, R 'is C1-C6-alkyl optionally substituted with phenyl, or phenyl, p is a value of 3, characterized in that the appropriately substituted starting compounds are used. A process for the preparation of a compound of formula (I) according to claim 2 wherein R is R "-A'-B'-, wherein R" is unsubstituted phenyl, A 'is a bond, B' is - CH ₂ -S (CH ₂ ) _m '-, m' is 2 or 3, R 'is C 1 -C 6 alkyl or phenyl optionally substituted with phenyl, p is 2 or 3, characterized in that it is suitably substituted starting compounds. (Priority: August 7, 1987) A process for the preparation of a compound of formula (I) according to claim 2 wherein R is R "-A'-B'-, R" is phenyl optionally substituted with one or two halogens, A 'is N a pyridylimino group, B 'is a group of the formula (CH ₂ ) _n ' -, n 'is 2 or 3, R' is a C 1 -C 6 alkyl or phenyl optionally substituted with phenyl, p is 2 or 3, characterized in that the appropriately substituted starting compounds are used. (Priority: August 7, 1987) 7. A process according to claim 2 for the preparation of compounds of formula (I) wherein R is R "-A'-B'-, R" is phenyl optionally substituted with one or two halogen atoms. . A 'is -CHR - képletfi formula, R ¹ is phenyl or pyridyl, B is - (CH2) n * - radical, n' is 2,3 or 4; R 1 is C 1-6 alkyl or phenyl substituted with phenyl, p is 2 or 3, characterized in that the appropriately substituted starting compounds are used. (Priority: August 7, 1987) A process for the preparation of a compound of formula (I) according to claim 2 wherein R is ptridyl-A "-B" -, A "is a bond, B" is -CH 2 -S- (CH 2) m "- wherein m" is 2 or 3; R 'is optionally substituted C 1 -C 6 alkyl or phenyl, p is 2 or 3, wherein the appropriately substituted starting materials are used. (Priority: 08.07.1987) A process for the preparation of a compound of formula (I) according to claim 2 wherein R is pyridyl-A "-B" -, A "is N- (mono-halobenzyl) -imino, B" is - (CH2) n '- wherein n' is 2, 3 or 4, R 'is C1-C6 alkyl or phenyl optionally substituted with phenyl, p is 2 or 3, characterized in that it is an appropriately substituted starting group compounds. (Priority: August 7, 1987) The process according to claim 2, N- [3- (imidazol-4-yl) -propyl] -N ² - [4- (pyrid-2-yl) -butyl] -N ³ -morcarbonyl-guanidine characterized in that the appropriately substituted starting materials are used. (Priority: August 7, 1987) A process according to claim 2 for the preparation of N ¹ 43 - (indidazol-4-yl) -pyridyl- ^{2 -} {4- (1-imidazol-2-yl) butyl] -N ³ -coxycarbonylguanidine. characterized in that appropriately substituted starting compounds are used. (Priority: August 7, 1987) The process according to claim 2, which is N- [3- (imidazol-4-yl) propyl) -N ² - [3,4-fluorophenyl] -3-pyridin-2yl) -butyl] -N-meth -carbonylguanidine, characterized in that the appropriately substituted starting compounds are used. The process according to claim 2, which is N- [3- (imidazol-4-yl) -propyl] -N ² - [4- (fluorophenyl) -3- (pyridin-2-yl) propyl] -N-ethoxy- Suitable substituted carbon starting materials are used in the preparation of carbonylguanidine. (Priority: August 7, 1987) 14. The process according to claim 2, N- (N-imidazol-4-yl) propyl] -N ² - [3- (4-fluorophenyl) -3- (pindin-2-yl) propyl] -N- butoxycarbonylguanidine, wherein the appropriately substituted starting materials are used. (Priority: August 7, 1987) 15. A process for the preparation of a pharmaceutical composition comprising a compound of formula (I) as defined in claim 1, wherein the substituents are as defined in claim 1, with a conventional carrier and / or excipient and / or other excipients. We converted. (Priority: 08.04.1988) 16. A process for the preparation of a pharmaceutical composition comprising a compound of formula (I) as defined in claim 2, wherein the substituents have the meaning given in claim 2, together with customary carriers and / or carriers and / or other excipients. We converted. (Priority: August 7, 1987)